1 Title 1 Subtitle 2 Chemotherapy Induced Cardiac Toxicity Russell Huntsinger, MD Cardiologist

2 What is Cardiac Toxicity? Damage to the heart muscle by a toxin is called cardiac toxicity. They may cause arrhythmias May lead to heart failure –Does not mean that that the heart has stopped or is about to stop –The heart muscle cannot pump with enough force to supply the body with blood containing essential oxygen and nutrients.

3 Chemotherapy Agents that Cause Cardiac Toxicity Doxorubicin (Adriamycin) Epirubicin Idarubicin Cyclophosphamide Fluorouracil Mitoxantrone

4 Anthracyclines Are the most common cause of cardiac toxicity in cancer patients.

5 Anthracyclines Used to treat a wide range of hematological and solid malignancies.

6 Chemotherapy drugs that have been reported to cause abnormalities in heart rhythm Gemtuzumab ozogamicin Paclitaxel Idarubicin Tyrosine kinase inhibitors Monoclonal antibodies

7 Occurrence Clinical heart failure generally occurs within a month to a year after anthracycline treatment. May occur up to years or later.

8 How is it diagnosed Heart sound – stethoscope Chest X-ray ECG Echo MUGA scan

9 What are the symptoms? Fatigue Shortness of breath on exertion Discomfort lying in supine Swelling of the ankles

10 Long cardiac toxicity can manifest as ventricular dysfunction and clinical heart failure.

11 Why? It is thought that direct myocardial injury is from free radicals.

12 How Can Cardiac Toxicity be Prevented Altering the amount of dose –Limit anthracyclines For example: if doxorubicin is less than 550mg/m2, there is a less than 1% chance of cardiac toxicity. If doxorubicin is between mg/m2, the risk increases to 30% Cur Med Chem. 2001;13:

13 Reported incidence of heart failure in adjuvant anthracycline therapy trials is 2% or less. Recent studies have reported 10-50% occurrence of subclinical decline in left ventricular function > 10% points after anthracycline treatment. J Am Coll Cardiol 2007; 50:1435

14 Reducing Drug Cardiotoxicity Structural modifications to the doxorubicin molecule (epirubicin). Incorporation into liposomes (doxorubicin) Development of structurally related drugs (mitoxantrone).

15 Method of Administration Evidence that the method of drug administration may affect the risk of cardiac toxicity. Rapid administration of drugs results in high blood levels, which may cause more heart damage than the same amount of drug given over a longer period of time. Small doses of drug, more frequently can decrease the toxicity compared to large doses of drugs at longer intervals.

16 Advancements in chemotherapy administration Liposomal anthracyclines are anthracycline encapsulated in a liposome. By enclosing in lipose, it stays in body longer due to the immune system doesnt target it for elimination and the liver doesnt break it down as quickly. Current studies indicate that the risk for heart problems is considerable lower with liposomal doxorubicin formulations than with conventional doxorubicin. Oncologist. 2003;8 Suppl 2:17-24.

17 Types of liposomal anthracyclines Liposomal daunorubicin (DaunoXome) Pegylated liposomal doxorubicin (Doxil) –Has been studied most extensively and has demonstrated the most significant reductions in heart problems –Has shown a similar anticancer effect to doxorubicin, but with less cardiac toxicity

18 Dexrazoxane (Zinecard) Has been shown to prevent or reduce the severity of heart damage caused by doxorubicin. Thought to protect the heart muscle by blocking the formation of oxygen free radicals.

19 Diagnostics Performed through echocardiogram. Abnormalities in diastolic dysfunction through Doppler. Cardiac biomarkers such as troponin or B- type natriuretic peptide (BNP) in monitoring chemotherapy induced cardiotoxicity is still be studied.

20 How is it treated Stopping or reducing the dose. Diuretics Digitalis drugs ACE inhibitors Beta-Blockers

21 Endomyocardial biopsy may be useful to help diagnosis anthracycline induced cardiotoxicity. Histological scaling has correlated with left ventricular function on radionuclide ventriculogram. Has limitations with availability of technique and high likelihood of missing the involved areas via biopsy. Dis Manage 2008; 11: 1-6

22 Survivorship and Cardiac Function As effectiveness of cancer treatment continues to improve, the population of long term survivors of childhood cancer will grow – an increase of late onset of cardiomyopathy will occur. Prognosis after heart failure is generally poor compared to that associated with idiopathic or ischemic cardiomyopathy.